Doctor Wang Medtech, Season 3, Episode 1, Rheumatoid arthritis（AP1189）
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease in which the immune system mistakenly attacks the body's own tissues. Patients develop synovitis due to autoimmune abnormalities that cause synovial damage to the joints. The main symptoms are joint swelling, stiffness and tenderness, often accompanied by morning stiffness. Patients in the middle and late stages will have "swan neck" and "button flower" deformities of the fingers.
RA usually affects not only the joints, but also extra-articular tissues such as mucocutaneous membranes, cardiovascular, lungs, nerves, eyes and blood systems, causing serious irreversible damage. Changes in prevalence and regional differences may be related to changes in risk factors, such as genetic factors, dietary factors, and lifestyle.
Epidemiological survey shows that the global incidence of rheumatoid arthritis is 0.5%~1%, the incidence of Chinese mainland is 0.42%, and there are currently about 5 million rheumatoid arthritis patients in China, and the ratio of men to women is about 1:4. With prolonged disease duration, the incidence of disability and functional limitations increases in patients with RA.
Due to the complexity of RA, the pathogenesis is not fully understood, and so far, no drugs have been developed that can fundamentally cure rheumatoid. At this stage, the treatment of rheumatoid is only aimed at maintaining the condition and relieving pain. Current clinical treatments for RA include: medication, surgery, and physiotherapy. However, drug therapy is still the mainstay, mainly including nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and biopharmaceuticals. Both NSAIDs and glucocorticoids have the effect of relieving pain and reducing inflammation. However, both these drugs need to be used in combination with DMARDs. The Chinese Guidelines for the Diagnosis and Treatment of Rheumatoid Arthritis recommend methotrexate as the first choice and take it as the basic drug for combination therapy. Hormonal therapy can be used as a "bridge" before the onset of DMARDs, or as a short-term measure when NSAIDs do not respond well, but it is not appropriate to treat rheumatoid arthritis with hormones alone, and DMARDs should be taken at the same time as steroids.
Back into the 50s of the 20th century, adrenocorticotropic hormone (ACTH) was firstly approved for the treatment of rheumatoid arthritis. ACTH is a peptide hormone produced and secreted by the pituitary gland and is an important chemical material in the hypothalamic-pituitary-adrenal axis. Moreover, as a physiological agonist of the melanocortitin system, it exerts different biological effects by combining with five different receptors (MC1R, MC2R, MC3R, MC4R, MC5R) and exerts anti-inflammatory effects. MC1R and MC3R are considered to be key receptors that directly affect the immune system, and these receptors are located on immune cells and related cells. When activated, MC1R and MC3R provide direct anti-inflammatory effects, which in turn stimulate pro-regressive effects. MC2R also exerts anti-inflammatory effects, but these effects are indirect. And MC2R is mainly located in the adrenal glands, and its stimulation causes the adrenal glands to release cortisol, which is the body's "natural" steroid, and although a powerful anti-inflammatory and immunosuppressive molecule, it is also a major factor in causing steroid adverse reactions. At present, adrenocorticotropic hormone is used clinically, and the reported adverse reactions mainly include allergic reactions, hypertension, pigmentation, hyperglycemia, acne and potential steroid hormone side effects, such as osteoporosis, obesity, Cushing's syndrome.
CREDIT data shows that 69.7% of RA patients in China take hormones for a long time (6 months), and 11.3% of patients use hormone monotherapy. Although glucocorticoids play an important role in the treatment of RA, they are also the most commonly used and abused, and long-term, large-scale, and irrational use of glucocorticoids will bring unimaginable consequences to patients. The 2018 Chinese guidelines for the diagnosis and treatment of rheumatoid arthritis mentioned that the problem of irregular glucocorticoid medication is still very prominent in China, and the use of glucocorticoids in the treatment of RA still needs to be further standardized. About 40%~60% of rheumatoid patients have been or are being treated with hormones. Many of these have led to dependence on hormones or have developed toxic side effects of hormones. However, abrupt withdrawal of the drug can not only cause rebound phenomenon, make the condition repeated or aggravated, but even lead to withdrawal crisis, that is, "iatrogenic adrenal insufficiency". Long-term use of exogenous hormones in large doses can cause adrenal atrophy or suppression of hypothalamic-pituitary-adrenal (HPA) axis response.
SynAct's lead drug candidate, AP1189, is an orally selective melanocorticoid agonist designed to stimulate MC1R and MC3R, rather than MC2R, thereby selectively stimulating melanocortin receptors directly involved in inflammation and their resolution, without stimulating the adrenal glands to release cortisol, helping to address excessive inflammation without steroid side effects and safety concerns. Since it achieves the purpose of anti-inflammation by stimulating the pathways involved in inflammation in the body, it also helps to restore the body's own anti-inflammatory function. In addition, AP1189 stimulates MC1R and MC3R by activating the pERK signaling pathway instead of the classical cAMP pathway. The cAMP pathway is a melanocortin pathway that causes off-target activities such as skin hyperpigmentation.
On November 30, 2021, SynAct announced the IIa study key results of AP1189, a 4-week study in which patients treated with 100 mg of AP1189 per day had a significant reduction in mean clinical disease activity score (CDAI) compared to placebo. The change in disease activity from severe to moderate was numerically higher in the group treated with AP1189 compared to placebo. Consistent dose-dependent effects were also observed in secondary readings, including disease activity scores DAS-28, ACR 20 scores, and FACIT fatigue scores. AP1189 was well tolerated and has good affinity, and no serious adverse reactions were reported.
Advantages and challenges
Advantage:
1. Clinical trials have preliminarily proved its efficacy and safety
2. The onset of action is relatively fast, and the administration is also more convenient
Clinical trials have shown that the effect can be achieved within a few days after administration, and the obvious effect can be seen within a month
3. As a replacement for ATCH, it reduces the adverse reactions caused by hormones, especially hormone abuse
Since it is not a hormone in itself, and only selectively stimulates melanocortin receptors directly involved in inflammation and their resolution, without stimulating the adrenal glands to release cortisol, helping to solve excessive inflammation without steroid side effects and safety concerns.
Challenge：
1. Existing clinical trials have not compared AP1189 head-to-head with hormones
Although SynAct did not say in its project introduction that its product positioning is to replace hormones, given that its clinical Ⅱa design is used in combination with MTX, I personally feel that it actually replaces some hormones or non-steroidal anti-inflammatory drugs, but this does not make a head-to-head comparison, perhaps the company will study it in future trials.
2. If the project is positioned as DMARD-IR or alternative DMARDs, it needs to be proved by experiments
The possible clinical positioning of the project is 1. DMARD does not respond or the patient is intolerant, 2. First-line use in some patients with specific RA. But if it is this positioning, then when the later clinical design is carried out, it is necessary to include this part of the patient and conduct targeted trials.
3.The company's research and development is mainly concentrated in a compound molecule, and in a relatively early stage, the development of multiple indications, on the surface the compound can be developed in many directions, but drug development is a high elimination rate process, with a bunch of early projects, not as good as 1-2 mature projects, which is more beneficial to late-stage financing or project transactions, and, more worriedly, once there are adverse reactions to break out, the impact on the entire R&D pipeline and the entire company will be huge.
The above is all the content of our current "Doctor Wang Medtech" program, the project still has certain characteristics, if it can really replace hormones, quickly eliminate inflammation, and do not produce immunosuppression, it is undoubtedly a gospel for RA patients, but the project has only completed clinical IIa, and it is necessary to show its advantages more fully through trials, hoping that everything will go well. In the next issue, we will return to the field of orthopedics and introduce you to a program for the treatment of discogenic chronic low back pain, which is currently in clinical phase IIb.
